Document Detail


Quantitative analysis of three-dimensional human mammary epithelial tissue architecture reveals a role for tenascin-C in regulating c-met function.
MedLine Citation:
PMID:  20042668     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Remodeling of the stromal extracellular matrix and elevated expression of specific proto-oncogenes within the adjacent epithelium represent cardinal features of breast cancer, yet how these events become integrated is not fully understood. To address this question, we focused on tenascin-C (TN-C), a stromal extracellular matrix glycoprotein whose expression increases with disease severity. Initially, nonmalignant human mammary epithelial cells (MCF-10A) were cultured within a reconstituted basement membrane (BM) where they formed three-dimensional (3-D) polarized, growth-attenuated, multicellular acini, enveloped by a continuous endogenous BM. In the presence of TN-C, however, acini failed to generate a normal BM, and net epithelial cell proliferation increased. To quantify how TN-C alters 3-D tissue architecture and function, we developed a computational image analysis algorithm, which showed that although TN-C disrupted acinar surface structure, it had no effect on their volume. Thus, TN-C promoted epithelial cell proliferation leading to luminal filling, a process that we hypothesized involved c-met, a proto-oncogene amplified in breast tumors that promotes intraluminal filling. Indeed, TN-C increased epithelial c-met expression and promoted luminal filling, whereas blockade of c-met function reversed this phenotype, resulting in normal BM deposition, proper lumen formation, and decreased cell proliferation. Collectively, these studies, combining a novel quantitative image analysis tool with 3-D organotypic cultures, demonstrate that stromal changes associated with breast cancer can control proto-oncogene function.
Authors:
Agne Taraseviciute; Benjamin T Vincent; Pepper Schedin; Peter Lloyd Jones
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-12-30
Journal Detail:
Title:  The American journal of pathology     Volume:  176     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-01-26     Completed Date:  2010-03-16     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  827-38     Citation Subset:  AIM; IM    
Affiliation:
Department of Cell Biology, Stem Cells, and Development, University of Colorado Denver, Aurora, Colorado, USA.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Aged, 80 and over
Breast Neoplasms / genetics,  metabolism,  pathology
Carcinoma, Ductal / genetics,  metabolism,  pathology
Cell Culture Techniques
Cell Proliferation
Cell Size
Cells, Cultured
Female
Gene Expression Regulation, Neoplastic
Humans
Imaging, Three-Dimensional
Mammary Glands, Human / cytology*,  metabolism,  physiology
Middle Aged
Models, Biological
Proto-Oncogene Proteins c-met / genetics,  metabolism,  physiology*
Tenascin / genetics,  metabolism,  physiology*
Young Adult
Chemical
Reg. No./Substance:
0/Tenascin; EC 2.7.10.1/Proto-Oncogene Proteins c-met
Comments/Corrections

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